14 HIV Intro/Drugs Mak Flashcards
What is the recommendation for initiating ART when looking at the CD4 count?
CD4 count < 350. Debatable when > 350
What is the recommendation for initiating ART regardless of CD4 count?
Pregnancy. History of AIDS-defining illness. HIV-associated nephropathy (HIVAN). Hepatitis B (HBV) coinfection. Age > 50 years
What happens with AIDS defining illnesses?
A patient with HIV and one of these illness automatically gets classified as having AIDS, regardless of CD4 count. Once in AIDS category, always in it, even if AIDS defining illness resolves
What are the general characteristics of CD4 count?
Major indicator of immune function. Assess trend and most recent CD4 count. A key factor in decision to start ART or OI prophylaxis. Important in determining response to ART (adequate response: CD4 increase 50-150 cells/uL per year)
When is CD4 monitoring done?
Check at baseline x2 and at least every 3-6 months
At what CD4 count is OI prophylaxis needed?
< 200
What are the general characteristics of VL?
VL influences decision to start ART and help determine frequency of CD4 monitoring. Critical in determining response to ART (Goal of ART: HIV RNA below limit of detection)
When is RNA (VL) monitoring done?
Check at baseline (x2); immediately before initiating ART. 2-4 weeks (no more than 8) after start or change of ART, then every 4-8 weeks until suppressed to < 200 copies/mL. Every 3-4 months if stable. Isolated “blips” may occur (typically < 400 copies/mL)
What happens when considering a deferral of ART?
Clinical or personal factors may support deferral (if CD4 count is low, deferral considered only in unusual situations, and with close follow-up). Significant barriers to adherence. Comorbidities complicate or prohibit ART. “Elite controllers” and long-term nonprogressors
What are the goals of ART therapy?
Improve quality of life. Reduce HIV-related morbidity and mortality. Restore a/o preserve immunologic function. Maximally, durably suppress HIV viral load. Prevent HIV transmission
What are the pretreatment evaluations for HIV?
HIV status (VL, CD4). CBC, CMP, UA, STDs, Hepatitis, Lipids. Opportunistic infections. PAP smear, prostate exam. Resistance testing. If indicated, or positive for risk factors: Psychiatric illness, substance abuse, comorbidities, economic and social support, adherence levels
What is done in resistance testing?
Genotype (detect drug resistance mutations that are present in the relevant viral genes). Phenotype (measure a virus’ ability to grow in various concentrations of ARVs, similar to bacterial C&S tests (shows IC50), compare with reference viruses (report fold increase cutoffs))
What is Drug Resistance Testing recommended?
Acute HIV infection, regardless of whether treatment is to be started. Chronic HIV infection, at entry into care. Pregnancy
What is HLA-B*5701 screening for?
Before starting Abacovir (ABC), to reduce risk of hypersensitivity reaction (HSR). Highest incidence in Caucasians and African Americans
What is a Coreceptor Tropism Assay for?
Performed when considering a CCR5 antagonist. Requires plasma HIV RNA >1,000 copies/mL. Consider in patients with virologic failure on a CCR5 antagonist (though does not rule out resistance to CCR5 antagonist)
What are the general characteristics of NRTIs?
All NRTIs need to be converted intracellularly to active triphosphorylated forms. MOA: inhibit transcription of vRNA into sdDNA. Not involved as P450 inducers or inhibitors. Renally eliminated. Little cross-resistance among NRTIs
What is toxicity usually like with NRTIs?
Mostly attributed to mitochondrial toxicity: Lactic Acidosis and Hepatomegaly with Steatosis are BBWs
What is Zidovudine (Retrovir)?
AZT, ZDV. NRTI. Durability about 12-24 months. Usually Co-Rx with 3TC (Combivir) and with 3TC/ABC (Trizivir)
What is Zidovudines undisputed efficacy in?
Preventing perinatal transmission. As postexposure prophylaxis. CSF penetration, higher dose needed for HIV associated dementia
What is the dosage like for Zidovudine?
300mg BID. Dosage reduced only in severe renal impairment
What are the ADRs associated with Zidovudine?
> 6-8 weeks: Hematologic toxicities: neutropenia and anemia. Lactic acidosis and Hepatomegaly with steatosis. Myopathy (increased CPK). Macrocytosis, hepatitis and hyperpigmentation of nails and skin (may indicate adherence). 1st month: N/V/A, HA, malaise, insomnia, confusion, flu symptoms
What is Didanosine (Videx EC)?
ddI. NRTI. Higher IC50 than ZDV (lower penetration into CSF than AZT, better activity vs. AZT in monocytes and macrophages). Acid labile, food limit absorption by 50%. Adjust dose based on weight and renal function
How is Didanosine dosed?
250-400mg QD
What is a DDI with Didanosine?
Concentration increased by TDF, but early virologic failure d/t resistance
What are the ADRs associated with Didanosine?
Pancreatitis. Lactic acidosis and hepatomegaly with steatosis, fatal in pregnant women concurrently on d4T and other NRTIs. Painful peripheral neuropathy, may resolve after several weeks. Non-cirrhotic portal hypertension, esophageal varices
What is Stavudine (Zerit)?
d4T. NRTI. Significant CSF penetration. d4T and ddl combination produced sustained virologic and immunologic benefits. Dosage based on weight and renal function
What are the DDIs associated with Stavudine?
Antagonistic with ZDV
What are the ADRs associated with Stavudine?
Pancreatitis. Lactic acidosis and hepatomegaly with steatosis (fatal in pregnant women concurrently on ddl). Peripheral neuropathy (dose dependent). Transaminase elevations, HA, NV
How is Stavudine dosed?
30-40mg BID
What is Lamivudine (Epivir)?
3TC. NRTI. VERY tolerable. Significant concentration achieved in CSF
Dosage reduction in renal impairment. Best tolerated NRTI. d4T and 3TC potent combination in ARV naive patients. Also indicated for Hepatitis B infection (acute exacerbation in treatment discontinued)
What is the best tolerated NRTI?
Lamivudine
How is Lamivudine dosed?
300mg QD
What are the ADRs associated with Lamivudine?
Lactic acidosis and hepatomegaly with steatosis. HA, diarrhea, occasional neutropenia
What is Emtricitabine (Emtriva)?
FTC. NRTI. Fluorinated analog of Lamivudine. Long intracellular half-life allows once daily dosing. Similar efficacy and problem for HBV as 3TC. Resistance and toxicity profile as Lamivudine. Included as part of a preferred NRTI backbone. Dosage adjustment in renal insufficiency
How is Emtricitabine dosed?
200mg QD
What are the ADRs associated with Emtricitabine?
Hyperpigmentation of palm and soles. Lactic acidosis and severe hepatomegaly with steatosis
What is Abacavir (Ziagen)?
ABC. NRTI. Comparable penetration into CSF as AZT. Dosage reduction recommended for hepatic insufficiency
How is Abacavir dosed?
300mg BID or 600mg QD
What are the DDIs associated with Abacavir?
Alcohol increases ABC level by 41%
What are the ADRs associated with Abacavir?
Lactic acidosis and hepatomegaly with steatosis. Fatal hypersensitivity reaction within 1st 6 weeks. (fever, rash, etc. HLA-B*5701 genotype before initiation. DO NOT rechallenge). MI, risk increases with pre-tx HIV RNA > 100,000
What is the only NRTI that doesn’t need renal adjustment?
Abacavir. Dosage reduction recommended for hepatic insufficiency
What is Tenofovir (Viread)?
TDF. NtRTI. Beneficial but not approved for HBV. Dosage adjustment in renal impairment (CrCl < 50)
How is Tenofovir dosed?
300mg QD
What are the ADRs assocaited with Tenofovir?
Lipodystrophy, Lactic acidosis and hepatomegaly, hepatitis. Renal insufficiency, Fanconi Syndrome (kidney problem with malabsorption). N/V/D. Flatulence. Asthenia. HA
What are the DDIs associated with Tenofovir?
Tubular secretion competition: ACV, GCV, metformin. Increased level of ddl. Decreased levels of 3TC, IDV, RTV, ATV. DRV increases levels of Tenofovir
What are the toxicities associated with ALL NRTIs?
Lactic acidosis and hepatic steatosis (BBW): d4T > ddl > ZDV. Pancreatitis (BBW). Peripheral neuropathy. Lipodystrophy
What is the only NRTI that has myopathy and bone marrow suppression?
AZT
What is the only NRTI to cause renal impairment?
TDF
What are the monitoring parameters for NRTIs and NtRTIs?
CBC with differentials. Metabolic panel. Hepatic panel. Amylase, Lipase. Anion Gap (ANG)/Lactate. Skin. Bone density
What are NRTIs most commonly used as?
Dual NRTI backbones, with 1 PI or 1 NNRTI
Which NRTIs have QD dosing?
ABC, ddl, 3TC, FTC, TDF
What are the more favored NRTIs used?
TDF, FTC > 3TC > ABC, ddl
What is the MOA of Protease Inhibitors?
Inhibits cleavage of polyproteins that is required for formation of infectious virions at the end of the HIV life cycle
How did the introduction of PIs change HIV treatment?
Dramatically reduced disease progression. Decreased hospitalizations; improve QOL. Decrease opportunistic infections; prolong survival. Significant viral suppression and improved CD4 even in advanced HIV disease
What is Saquinavir (Invirase)?
SQV. PI. Old, not used much. High fat meal increases levels 6x, take within 2h of a meal. Least potent PI, requires boosting with RTV. Alternative PI for pregnant women. Poor BA
When is Saquinavir contraindicated?
In severe hepatic impairment
What are the DDIs associated with Saquinavir?
Levels increased by 3A4 inhibitors (e.g. RTV). Levels decreased by 3A4 inducers (e.g. Rifabutin, anticonvulsant, EFV, NVP)
What are the ADRs associated with Saquinavir?
N/D, abdominal pain, HA. Higher dose or with RTV: diarrhea, cough, rash, and increased LFTs. Metabolic abnormalities. Increased bleeding risk in hemophiliacs. PR/QT prolongation, need baseline EKG
How is Saquinavir dosed?
1000mg + 100mg RTV BID
What is Ritonavir (Norvir)?
RTV. PI. Food minimizes GI side effects, increases bioavailability (separate from antacids and ddl)
How is Ritonavir dosed?
600mg BID
What are the DDIs associated with Ritonavir?
Most potent 3A4 inhibitor (advantageous to boost combination regimen (dosed 100mg), potential for fatal drug interactions). Inhibits pgp. Induces glucuronosyl transferase (decreased efficacy of oral contraceptives). Avoid use with Rifampin
What can the alcohol content in the Ritonavir solution cause?
Alcohol content in solution formulation can induce disulfiram reactions
What are the ADRs assocaited with Ritonavir?
Circumoral and peripheral paresthesia, asthenia, fatigue, HA. N/V/D/A, abdominal pain, taste disturbance. Muscle weakness or pain, renal dysfunction. Metabolic abnormalities. Risk of bleeding with hemophiliacs
What is a potential interaction with Fluticasone and Ritonavir?
Fluticasone induced Cushing’s Syndrome. Fluticasone is a 3A4 substrate and RTV a 3A4 inhibitor
What is Indinavir (Crixivan)?
IDV. PI. “Unfriendly”, not used much anymore. BA reduced with food by 77% (take on empty stomach, RTV boosting eliminates food restriction). Dose reduced to 600mg TID in liver impairment. Substrate and inhibitor of 3A4
How is Indinavir dosed?
800mg TID
What are the ADRs associated with Indinavir?
Nephrolithiasis (drink plenty of water). Indirect hyperbilirubinemia. Mild GI disturbance. Metabolic abnormalities. Jaundice or hepatitis warrant discontinuation of drug. Risk of bleeding with hemophiliacs
What is boosted regimens with Ritonavir like?
Using RTV to inhibit metabolism of other PIs (reducing effective dosage (pill burden), reducing dosing frequency, enhancing ability to adhere). Boosted PIs generally recommended unless: intolerable ADRs, sustained undetectable VL
What is Lopinavir?
LPV. PI. Potent and good virologic experience; a preferred PI based component dosed BID for pregnant women. Available in tablets or oral solution (oral solution contains 42% alcohol, watch for disulfiram effects)
How is Lopinavir dosed?
200mg combined w/ 50mg RTV as Kaletra tabs or 4 tabs QD
What are the disadvantages of Lopinavir?
Metabolic complications. GI intolerance. Elevated LFTs. Potential bleeding risks in hemophiliacs. Lower drug exposure in pregnant women. Risk of MI. Significant drug interactions
What is Nelfinavir (Viracept)?
NFV. PI (one of the preferred ones). Combination with d4T better efficacy than d4T alone. Food increases levels by 2-3x. Similar potency as ATV and RTV-boosted fos-APV. Inferior to Kaletra, EFV
How is Nelfinavir dosed?
1,250mg BID
What are the DDIs associated with Nelfinavir?
3A4 substrate and inhibitor. Increases SQV AUC about 4x, strategic combination
What are the ADRs associated with Nelfinavir?
Mild to moderate diarrhea!!! Metabolic abnormalities. Increase LFTs. Risk of bleeding in hemophiliacs
What is Fosamprenavir (Lexiva)?
FPV. PI. Rapid response (rapid 2.0 log reduction plasma HIV-1 viral load, > 100 cells/mm3 increases in CD4 cells). Dosing flexibility - with or without RTV. Well tolerated (no food effect, rash (similar to other PIs, but less common). Dose reduction with hepatic impairment
What are the disadvantages to Fosamprenavir?
Cross-resistance with Darunavir (DRV). Sulfa sensitivity
What is the dosing of Fosamprenavir?
Boosted: 1,400mg + 100 or 200mg RTV QD or 700mg + 100mg RTV BID. 1,400mg BID: unboosted, acceptable for naive patients
What is Atazanavir (Reyataz)?
ATV. PI (one of the favorites) Food increases BA (PPIs decrease effects). Dose reduced to 300mg in Child Pugh B; not recommended in Child Pugh C)
What are the advantages of using Atazanavir?
Improve lipids! Easy QD dosing. Good GI tolerability. Signature PI mutation (l50L) not associated with ATV resistance
What are the DDIs associated with Atazanavir?
3A4 inhibitor and substrate. Levels decreased by TDF and EFV, need boosting w/ RTV. Increase levels of warfarin, TCAs
What are the ADRs associated with Atazanavir?
Indirect hyperbilirubinemia. Asymptomatic 1st degree AV block. Nephrolithiasis. Metabolic disturbance except for lipid abnormalities
What is Tipranavir (Aptivus)?
TPV. PI. Indicated with RTV for EXPERIENCED patients w/ evidence of viral replication or w/ resistance to multiple PIs. Refrigerate before opening; stable x60 days in RT. 3A4 substrate
How is Tipranavir dosed?
500mg TPV + 100-200mg RTV BID with food
What are the ADRs associated with Tipranavir?
Typical PI family ADRs
When is Tipranavir contraindicated?
In patients with sulfa allergy and moderate to severe hepatic impairment (Child Pugh B/C)
What are some counseling points for Tipranavir?
Antacids may decrease TPV/RTV absorption, separate dosing. Keep in refrigerator or store at room temperature for up to 60 days. ADRs and contraindications; need frequent LFT monitoring
What is Darunavir (Prezista)?
DRV. PI. Indicated for treating EXPERIENCED patients w/ resistance to > 1 PI initially. Also for treatment naive patients. Not recommended in severe hepatic impairment. Sulfonamide moiety; contraindicated in pts w/ sulfa allergy
How is Darunavir dosed?
600mg DRV + 100mg RTV BID
What are the ADRs associated with Darunavir?
Hepatotoxicity! Increased LFTs! Rash, N/D, HA, common cold; other ADRs as in PI family
What are the DDIs associated with Darunavir?
May increase TDF AUC, Cmax and Cmin. Decrase [paroxetine] and [sertraline]
What are the monitoring parameters for PIs?
Hepatic panel. Metabolic panel. Lipid panel (recommended 4-8 weeks after initiation or changed therapy). CBC with differentials. PT/APTT. UA. Skin
What are the advantages of PIs?
Higher genetic barrier to resistance. PI resistance uncommon with failure (boosted PI). NNRTIs and II preserved for future use
What are the disadvantages of PIs?
Metabolic complications (fat maldistribution, dyslipidemia, insulin resistance). GI intolerance. Potential for drug interactions (CYP450), especially with RTV. Pill burden
Which PIs must be dosed with RTV?
SQV, LPV, TPV, and DRV
What are the more favored PIs?
LPV. ATV. DRV
What are the 1st generation NNRTIs?
Nevirapine and Efavirenz
What are the 2nd generation NNRTIs?
Etravirine and Rilpivirine
What is Efavirenz (Sustiva)?
EFV. 1st gen NNRTI. Recommended as a “protease sparing” alternative. High fat meals increase absorption (take on empty stomach to reduce ADRs); therapeutic CSF level. 3A4 inducer > inhibitor
How is Efavirenz dosed?
600mg QD, bedtime recommended
What is resistance like with Efavirenz?
Cross-resistance with other NNRTIs likely
What are the ADRs associated with Efavirenz?
Early CNS effects including dizziness, vivid dreams or nightmares, ‘disconnections’; may be exacerbated by high fat meals. False + cannabinoid and BZD test results. Pregnancy Category D. Rash. Increased LFTs
What is Nevirapine (Viramune)?
NVP. 1st gen NNRTI. Triple regimen with 2 NRTIs effective, PI sparing. Acceptable CSF penetration
What is resistance like with Nevirapine?
Emerges rapidly unless virus completely suppressed. Cross-resistance with other NNRTIs
What are the ADRs associated with Nevirapine?
Erythematous, maculopapular rash; severe, fatal skin reactions: SJS, toxic epidermal necrolysis. Systemic hypersensitivity reactions (1st 18 weeks crucial). Fatal hepatotoxicity (increased risk in pregnancy, women w/ CD4 > 250, men w/ CD4 > 400)
What is Etravirine (Intelence)?
ETR. 2nd gen NNRTI. Indicated for treating EXPERIENCED patients failing 1st gen NNRTI and other ARVs
How is Etravirine dosed?
100mg and 200mg tabs; 200mg BID after meals
What are the ADRs associated with Etravirine?
Rash, nausea, hypersensitivity reaction
What are the DDIs associated with Etravirine?
Substrate and inducer of 3A4. Inhibitor of 2C9, 2C19. Do not use with boosted PIs. May prevent activation of clopidogrel, avoid concomitant use
What is Rilpivirine (Edurant)?
RPV. 2nd gen NNRTI. Indicated in combination with other ARVs for treatment-naive adult patients. Higher failure rate in patients with BL HIV VL > 100,000 copies. Pregnancy Category B
How is Rilpivirine dosed?
25mg tabs: 25mg QD with a meal
What are the ADRs associated with Rilpivirine?
Depression, insomnia, HA, rash
What are the DDIs associated with Rilpivirine?
Substrate of 3A4. Avoid use w/ drugs that increase gastric pH
Besides the regular NNRTI ADRs, what is specific to Rilpivirine?
Depression
What are the monitoring parameters for NNRTIs?
Skin. Hepatic panel. Mental status. Metabolic panel. CBC with diff. CD4. Pregnancy test for female patients on EFV!
What are the advantages of NNRTIs?
Long half-lives. Less metabolic toxicity (dyslipidemia, insulin resistance) than with some PIs. PIs and II preserved for future use
What are the disadvantages of NNRTIs?
Low genetic barrier to resistance - single mutation. Cross-resistance among most NNRTIs. Rash; hepatotoxicity. Potential drug interactions. Transmitted resistance to NNRTIs more common than resistance to PIs
What is the NNRTI based preferred regimen with 2 NRTIs backbone?
EFV
What is Enfuvirtide (Fuzeon)?
First fusion inhibitor. Indicated in a combination regimen for adults and children > 6 years
What is the MOA of Enfuvirtide?
Inhibits the fusion of viral and cellular membranes, blocking the viral ability to infect certain components of the immune system
How is Enfuvirtide dosed?
90mg SQ BID. SQ injection presents limitations (local site reaction intolerable)
What ADRs is Enfuvirtide associated with?
More bacterial pneumonia and allergic reactions
What is Maraviroc (Selzentry)?
CCR5 co-receptor antagonist: binds to the CCR5 receptor on the membrane CD4 cells. Use of Maraviroc should be based on treatment history and tropism assay results; 3A4 substrate dose dependent on concomitant meds
What is the indication for Maraviroc use?
Indicated (in combination with other ARVs) in adult HIV-infected patients, with detectable CCR5-tropic HIV-1 only
What are the ADRs associated with Maraviroc?
Hepatotoxicity after systemic allergic reaction. Abdominal pain; musculoskeletal symptoms. URI; cough. Dizziness/postural hypotension
How is Maraviroc dosed?
300mg BID
When is a Tropism Assay recommended?
CCR5 inhibitor is considered. Patients fail on CCR5 inhibitor
What are the advantages of Maraviroc?
Virologic response noninferior to EFV. Fewer adverse events than with EFV. NNRTIs, PIs, and IIs preserved for future use
What are the disadvantages of Maraviroc?
Requires tropism testing before use. Less experience that with boosted PI- or NNRTI-based ART. BID dosing. CYP 3A4 substrate; dosage adjustment required if concomitant inducers or inhibitors
How do Integrase Inhibitors (IIs) work?
Inhibit the covalent linkage of viral DNA to chromosomal DNA; active at nM concentration
What are the advantages of Integrase Inhibitors?
No known cross-resistance with other antiretroviral classes. Fewer ADRs and lipid effects than EFV; fewer DDIs. Target third essential enzyme for HIV replication (reverse transcriptase, protease, integrase). Oral administration, no food restriction
What are the disadvantages of IIs?
Long-term adverse effects not yet defined. Viral resistance likely with failure; genetic barrier to resistance. Risk for cross-resistance within class
What is Raltegravir (Isentress)?
RAL. II
How is Raltegravir dosed?
400mg BID
What are the ADRs associated wtih Raltegravir?
CPK elevations (rhabdomyolysis, myopathy). N/D. HA, pyrexia. Rash
What are the drug interactions with Raltegravir?
Eliminated by glucuronidation. Concentration reduced by Rifampin (increase dose to 800mg BID)
